phthalates and ADHD

The outstanding debate on whether the benefits of soft plastics outweigh their potential harms continues. 

The group of esters called phthalates are used in an array of products ranging from pill capsules to children's toys to shower curtains.  A research group in Korea has found a strong positive correlation between ADHD behavioral characteristics and phthalate metabolites in the urine of Korean school children.  This is a particularly important study for two reasons: 1) a correlation between ADHD and phthalate exposure during critical periods of development has never been shown, and 2) the metabolite levels found in these children indicates the amount of exposure that can now be replicated in animal models.

"Previous animal studies (6,15,16) have shown that phthalate related metabolites induce hyperactivity in rats. These studies reported that pups treated with phthalate demonstrated 1.4 times the level of hyperactivity at night compared with control subjects. Such hyperactivity was dose-dependent, which is consistent with the results of our study."

"It is possible that the toxicity of phthalates is attributable to degeneration of dopaminergic neurons, leading to the hyperkinetics observed in rats in cases of 6-hydroxydopamine (OHDA) procedures (27). Well-known animal models of ADHD like the OHDA rat model suggest that the dopamine neuronal damage can provoke hyperactivity and impulsivity. Many structural magnetic resonance imaging studies showed striatal volume loss suggesting the dopamine neuronal loss in ADHD patients (28)."

"With DNA macroarray data, researchers have found that phthalate metabolites change
the expression patterns of various genes, including both the dopamine receptor D4 (DRD4) and the dopamine transporter in the midbrain (6). The dopamine receptor D4 and dopamine transporter gene expression modulation can induce changes in extracellular dopamine and neuronal dopamine sensitivity, resulting in hyperactivity and impulsivity in rats."

Here is something particularly interesting: if excessive exposure to phthalates is linked causally to ADHD phenotypes -- which has yet to be explored -- perhaps the time-release medications used to treat ADHD such as Wellbutrin and Ritalin should cease to use phthalates in the enteric coating of their medications.  It seems odd that they are so widely used in films of pharmaceutical capsules if for no other reason than their heavy reputation as endocrine disruptors.  Capsules can contain in the range of 3600 ug phthalates, while most studies estimate that the "safe" exposure range is near 20 ug per kilogram body weight.  That means the "safe" range for most young children is about 750 ug.  Note that phthalates do not bioaccumulate, so exposure levels are dailies.

"The bupropion (Wellbutrin® SR)  release rate has been improved by the introduction of two types of film coated active pellets that release the drug at different pH resulting in novel dissolution profiles. Inert spheres are initially coated with bupropion and hydroxypropyl methylcellulose. The active pellets containing bupropion comprise 70-75 weight % of the dosage form. An enteric coating, applied to about one third of the active drug pellets, is comprised of a film insoluble at low pH, such as hydroxypropyl methylcellulose phthalate. The second coating applied to the other two thirds of active drug pellets is comprised of a combination of a hydrophobic coating agent and methyl acrylic acid copolymer. The two pellet types are then combined in a capsule."

"The novel dosage forms are used to administer methylphenidate (Ritalin) in a pulsatile release manner... Suitable membrane coating materials for effecting delayed release include, but are not limited to: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, cellulose ester-ether phthalate, hydroxypropylcellulose phthalate, alkali salts of cellulose acetate phthalate, alkaline earth salts of cellulose acetate phthalate, hydroxypropylmethyl cellulose hexahydrophthalate, cellulose acetate hexahydrophthalate..."

Journal Club: on the selective degeneration of dopamine neurons in Parkinson's disease

http://www.ncbi.nlm.nih.gov/pubmed/16299504

The therapeutic application of potassium gated ATP channels (K-ATP) in Parkinson's disease arises from their ubiquitous expression in the basal ganglia.  Regulation of these channels evokes cell hyperpolarization in order to prevent cell excitability.  In the mitrochondria, they play a role in translating the metabolic state of the neuron.  This week's journal club discussed an article suggesting that K-ATP channels are necessary for the selective vulnerability of dopamine neurons in the substantia nigra pars compacta (SNpc) relative to the ventral tegmental area (VTA).   Liss et al demonstrate this theory using mitrochondrial complex I inhibitors rotenone and MPP+, both neurotoxins commonly used in developing Parkinson's disease models in rodents.

Rotenone and MPP+ are known to selectively degenerate dopamine neurons of the SNpc, leaving the VTA dopamine neurons primarily in tact.  Liss et al suggest that this phenomenon is due to differential mitochondrial uncoupling (or, disruption of metabolism).  Extensive uncoupling with the application of FCCP resulted in activation of K-ATP channels in both the SNpc and VTA.  Mild uncoupling with FCCP did not activate K-ATP channels in either region.

"Notably, however, mild uncoupling inverted the response of K-ATP channels to complex I inhibition: in this case, VTA DA neurons, but not SN DA neurons, were hyperpolarized and functionally silenced due to K-ATP channel activation. In the presence of 50 nM FCCP, none of the SN DA neurons was significantly affected by 100 nM rotenone (Fig. 5a,b, left; perforatedpatch recording in 50 nM FCCP: 2.33 ± 0.29 Hz; FCCP + rotenone: 1.92 ± 0.36, n ¼ 6; P ¼ 0.40) or 10 mM MPP+ (data not shown). In contrast, the presence of 50 nM FCCP sensitized K-ATP channels of VTA DA neurons to complex I inhibition (Fig. 5a,b, right; 50 nM FCCP: 2.4 ± 0.55 Hz; FCCP + rotenone: 0 ± 0 Hz, n ¼ 6; P ¼ 0.0075)."

"Stereological analysis of all SN pars compacta neurons in hematoxylin-eosin counterstained sections demonstrated genuineMPTP-induced neuronal death in wildtype mice and confirmed the complete rescue of SN neurons in the Kir6.2-/- mice (Fig. 6d, middle panel; Kir6.2+/+ SN: control, 11,882 ± 222; post MPTP, 8,061 ± 632, P ¼ 0.029; Kir6.2 -/- SN: control, 12,288 ± 231; post-MPTP, 12,619 ± 223; P ¼ 0.36; n ¼ 3 each)." ** Kir6.2 -/- mice are a genetic strain not expressing a unit of the K-ATP channel necessary for activation.  This means that blocking the channel's activity prevented SN DA neurons from being lost.

I want to see some apoptosis markers in these SNpc DA neurons due to K-ATP activity.  The comaprison of SNpc and VTA DA neurons is an invaluable resource for identifying mechanisms of the selective degeneration that marks Parkinson's disease.  Because the VTA DA neuron population is so identifiably unaffected by most neurotoxins from which Parkinson's models are developed, the selectivity of the models and the degree of neural degeneration is not only measurable but comparable to many cellular mechanisms of the disease itself.  Uncoupling of the mitochondria speaks to selective metabolic toxicity, and a new target for neuroprotective therapies.

** This was a very complex article using six different mouse strains/treatment groups and analyzing the cell viability using electrophysiology, histology and RT-PCR -- I am reciting only the briefest summary which does not to justice to the extensive work done (although my critique is long-winded, I was impressed with these studies).

on the stifling of creativity

An experiment was conducted by Desmond Morris in 1962 comparing the artistic creativity of young children and chimpanzees.  Remarkably, both chimp and human child became so engrossed in their painting that they showed very little interest in food, sex or other activities that would be expected to divert their interest.  The major revelation of this study was that creativity was, perhaps, a natural potential; yet, for many of us, the urge to create diminishes significantly as we grow older, revealing itself only in the sciences, music, art... and on a more modern note, advertising [trash].

A follow-up study to Morris' added a reward system to the chimps' sessions of abstract expressionism.  The results was that with each reward, the creativity and depth of the painints degenerated until producing only the minimal product necessary to obtain reward from the experimenter (The Biology of Art, Methuen London, 1962).

David Bohm has described this phenomenon as follows:

"In order to do something for a reward, the whole order of the activity, and the energy required for it, are determined by arbitrary requirements that are extraneous to the creative activity itself.  This activity then turns into soemthing mechanical and repititious, or else it mechanically seeks change for its own sake.  The state of intense passion and vibrant tension that goes with creative perception... then dies away.  The whole thing becomes boring and uninteresting so that the kind of energy needed for creative perception and action is lacking.  As a result, even greater rewards or punishments are needed to keep the activity going" (Science, order and creativity; 2000).

I've written about ADHD before, but was inspired to revisit the topic by a seminar forwarded to me:

http://www.ted.com/talks/lang/eng/ken_robinson_says_schools_kill_creativity.html

So my question is this: to what extent is the reward system of education -- any kind of education -- destructive to the development of the self?  Is not the self-consciousness, dissatisfaction and boredom resulting from intervention by directed creativity dangerous to development? Some of what were considered the greatest creative minds of history thwarted standardized education.  From the science realm alone (with which I am most familiar), Copernicus meandered through universities for seven years without bothering to fulfill a degree.  Da Vinci was educated by the royal Medici family, but education in the Italian Renaissance was its own matter entirely.  Tesla boycotted academia at the age of ten.  Thomas Edison never went. 

On the other hand, in more recent history it has become nearly impossible to achieve recognizable creativity without eons of academic vigor.  How is that demand defining the way we structure the reward system of education?  We pump in the sedatives to get this "most troubled" generation through the hoops.  In so doing, we are pummeling creativity from both ends: reward and sedation.  What will become of our next generation of scientists and artists?

autism spectrum disorders, part deux

Another instance where the question begs to be asked: are handwriting patterns differentiated between autistic and Asperger children?

This study found quality of letter formation in the handwriting of children with ASD to be lower than in normally developing children.  The subject hasn't really been addressed since 2001, when Beversdorf et al identified the significant instance of macrographia in patients with ASD, as compared to age- and IQ-matched control subjects.  Both studies have subsumed autism and Asperger into the ASD umbrella -- just as likely for the purposes of procuring a larger test subject sample as for making their results widely applicable:

"Whereas all subjects with autism spectrum disorder met the diagnostic criteria for autism through their reported behavior during childhood, most subjects had demonstrated significant improvement in function over time, such that the distinction between the various forms of autism spectrum disorder was not as clear. Therefore the more general term autism spectrum disorder is used to describe these patients." (Beversdorf)

The original description of Asperger syndrome in 1944 noted difficulties in motor coordination, specifically in handwriting (Frith; translated 1991).  One year before, Leo Kanner published his first paper asserting that some autistic children were quite agile, performing "hair-raising feats of balancing," while others were clumsy "despite dextrous manipulation of objects" (Frith pg. 95). 

I would love to see a study comparing the different aspects of handwriting using both the Revised Physical and Neurological Examination for Subtle Sign (from the Kennedy Krieger Institute study), and the Autism Spectrum Quotient and Empathy Quotient tests used by Baron-Cohen's group to differentiate autism and Asperger syndrome.  Any cerebellar distinctions between autism and Asperger could be very illuminating...

autism spectrum disorders and dsm-v politics

An article in the New York Times this morning by Simon Baron-Cohen addressed the debate in the DSM committee over subsuming the conditions of Autism and Aspergers in the fifth edition of the "psychiatric bible"(promised in 2012).  The committee is deliberating whether or not to eliminate Asperger from the diagnostic manual and characterize its discrete symptoms as a degree of autism in the spectrum (perhaps "intermediate functioning autism").

Autism and Asperger syndrome are both characterized by impaired communication skills, a desire for keenly focused stimuli and strong inclination toward repetition. They are distinguished only by a slower onset of language skills and latency of intelligence in autism, says Baron-Cohen.  He further suggests that this distinction is proving not to be concrete enough, and that the DSM-V committee's struggle with the controversy can be attributed to the lack of physiological distinction of these psychiatric conditions.

I would agree with Baron-Cohen that there is not currently enough genetic distinction between autism and Asperger syndrome to warrant their being entirely separate conditions outside the spectrum disorders umbrella in the DSM-V.  However, I think that defining Asperger syndrome idiosyncratically is important to preserve in the new manual.  Here is why:   

1)  Baron-Cohen mentions his own group's recent identification of 14 Asperger-specific genes,19 genes specific to autism and 7 shared (Chakrabarti et al 2009).  They measured 68 candidate genes in two experiments: the first measured autistic traits in an undiagnosed sample population using the Autism Spectrum Quotient; the second, using the Empathy Quotient.  These two experiments were designed to identify autistic and Asperger cases among the sample:

"We searched for common genetic variants (single nucleotide polymorphisms (SNPs)) on the assumption that autistic traits are continuously distributed in the general population [Constantino & Todd, 2005; Sung et al., 2005]."

"In Experiment 1, autistic traits (measured on AQ and/or EQ) were nominally associated at P<0.05 with SNPs from 19 genes. In Experiment 2, SNPs from 14 genes were nominally associated at P<0.05 with AS."

Six genes were nominally significant in both experiments. This study alone suggests that Asperger syndrome deserves a distinction as a sub-group in the Autism Spectrum Disorders (ASD) category that the DSM-V committee is considering, as opposed to eliminating it entirely, as is also being considered.

The Charkrabarti study is impressive, and the first step in the important attempt to identify the genetic and epigenetic correlates of autism and Asperger separately.  However, there is still an extensive amount of correlative research to be done.  A good amount of this is ongoing through the AutDB Project.

2)  If for no other reason than to preserve the honor of the venerable Hans Asperger.

3)  To keep company the solitary other recognized ASD, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS).*  Perhaps these could both become sub-groups in the ASD category.

It is noteworthy that a great deal of genetic research already refer to their studies as ASD interactions/links/correlations (PubMed or Google Scholar this).  I am terribly eager to find out whether or not this plays a strong role in the decision of the DSM-V committee.


*High- and Low-functioning autism are not classified as spectrum disorder subgroups, although they should be... and perhaps, one day, will be, provided there is a physiological distinction to be drawn between them, Asperger and PDD-NOS.

Journal Club: on Vitamin D and Parkinson's disease

Preface:  After a long hiatus during which I have been doing so much research on Crohn's disease that I haven't written a damn thing about neuroscience, I've decided that it's time to return.  I have officially submitted my graduate school applications, and now need to get myself back into regular science-writing mode.

This week's Movement Disorders Journal Club held some lively discussion on the roles that vitamin D might play in the balance deficits of Parkinson's disease patients.  This was based on data presented for a grant application, so the following will have little to do with Dr. P's actual pilot study.

Vitamin D deficiency appears to be prominent in elderly people who frequently experience falls (Bischoff-Ferrari et al 2004).  The mechanisms by which vitamin D is involved with balance, however, are largely unknown.  Dr. P's studies propose to look at how vitamin D levels correlate with falls and posturography in patients with Parkinson's disease (PD) because post-mortem immunolabeling studies have shown that vitamin D receptors are particularly dense in the substantia nigra pars compacta (SNpc)(Eyles et al 2005).

The SNpc is an area of primary pathology in PD; specifically, it is the beginning of the primary dopamine pathway that extends to the basal ganglia and motor cortex, which ultimately make commands of the muscles.  When this pathway is depleted, as in PD, the lack of dopamine signaling from SNpc cells has ramifications through several terminal brain regions which lead to the rigidity, tremor and poor balance that characterize the disease.

One of the important questions to ask, given the high vitamin D receptor density in the SNpc, is what role vitamin D might play in that region of the brain: Is there a central nervous system mechanism by which vitamin D is involved in alleviating behavioral deficits of PD, or is vitamin D helping patients with more general balance deficits through its effect on muscles?

Dr. P is proposing to address this question on both clinical and basic science levels.  Her clinical studies will address the attenuation of several behavioral and motor impairments as correlated with various vitamin D levels.  Her complementary basic science component proposes to speculate vitamin D's activity in the SNpc of a rodent model.  Naturally, this is super exciting to yours truly, so I have offered my services (as an MD, Dr. P needs a collaborative basic science lab in which to conduct the non-human animal component of her studies).  It stunned me, in fact, to learn how little has been studied regarding the role of vitamin D in the SNpc and nigrostriatal pathway, given the clear indication that its receptors are prevalent.

Although this will not begin for several more months, at least, there will be more to come as the publishable results unfurl.  In the meantime, expose yourself to the sunshine! -- you supposedly benefit more from 15min/day sun exposure than from dietary means (Hall et al 2009; Wolpowitz & Gilchrest 2006).  Fanatic Cook elaborates on this beautifully.